tbuckley/cabot-search huggingface dataset:
Abstract 802: Development of replication protein A (RPA) targeted PROTACs for the treatment of lung and ovarian cancers
Authors: Jeremy M. Kelm, Jitender Dev Gaddameedi, Pamela S. VanderVere-Carozza, Amirreza Samarbakhsh, Nivisa Vakeesan, Hussein W. Kansou, Sara Serafimovski, Katherine S. Pawelczak, John J. Turchi, Navnath S. Gavande
Journal: Cancer Research (2022)

Abstract Despite remarkable advances within the field of molecular cancer therapeutics over the preceding decades, DNA-damaging agents retain a central role in the pharmacotherapy of neoplastic diseases. The clinical response to DNA-damaging therapies is varied within and across cancer subtypes where a robust DNA damage response (DDR) predicts recalcitrance. Replication protein A (RPA) is the predominant human single-stranded DNA (ssDNA)-binding protein, playing essential roles in DNA replication, repair, recombination, and the DNA-damage response (DDR). Inhibition of the RPA−DNA interaction is an approach to cancer drug discovery that holds potential to provide single-agent activity and/or synergy with existing therapeutics. Proteolysis targeting chimera (PROTAC) based drug design presages a paradigm shift within drug discovery as PROTACs begin to carve out a space in the clinical landscape. The PROTAC platform is particularly suited for drugging overexpressed proteins such as RPA because iterative target degradation improves drug:target stoichiometry and precludes RPA’s role in protein scaffolding. Herein, we describe the synthesis and biological evaluation of an RPA targeted PROTAC library conceived by conjugation of the diaryl pyrazole RPA inhibitor TDRL-551 and an E3-ligand via a linker of variable length and composition. Residing within the beyond rule of five (bRo5) chemical space, careful consideration was given to minimize the liability to cell permeability imposed by the high molecular weight of PROTACs. Excitingly, cellular uptake across the compound library was broadly improved relative to the unconjugated warhead TDRL-551. Similarly, RPA engagement by the PROTAC series was widely unhindered and, in many cases, improved relative to the warhead TDRL-551. A subset of the compound library unified by flexible linkers and alkyne attachment of the E3-ligand (typified by GL-3311) display low single-digit micromolar IC50 values in viability assays across H460, A549, and A2780 cell lines. Citation Format: Jeremy M. Kelm, Jitender Dev Gaddameedi, Pamela S. VanderVere-Carozza, Amirreza Samarbakhsh, Nivisa Vakeesan, Hussein W. Kansou, Sara Serafimovski, Katherine S. Pawelczak, John J. Turchi, Navnath S. Gavande. Development of replication protein A (RPA) targeted PROTACs for the treatment of lung and ovarian cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 802.
Abstract 3494: Characterizing the relationship between genotype and phenotype in DNA damage response-altered pancreatic cancer models
Authors: James R. Carroll, Jason M. Link, Jonathan R. Brody
Journal: Cancer Research (2022)

Abstract Alterations in DNA damage response (DDR) proteins are prevalent across cancers and present unique opportunities for the therapeutic induction of synthetic lethality (i.e., two gene deficiencies in the same pathway synergize to kill tumor cells). In pancreatic adenocarcinoma, patients harboring alterations in DDR genes, such as in homology-directed repair (HDR), comprise the 10-20% of patients that may benefit from the recent FDA approval of Olaparib, a poly (ADP-ribose) polymerase inhibitor that disrupts non-homologous end joining (NHEJ). Despite being the best-in-class targeted therapy for DDR-altered pancreatic cancers, a subset of patients fails to respond to Olaparib and those that initially respond eventually go on to develop resistance. The mechanisms underlying resistance are poorly elucidated but suggest that some patients harboring DDR-altered tumors are HDR-proficient or revert to HDR-proficiency during therapy, bypassing the second gene deficiency requisite for synthetic lethal induction with targeted therapy (e.g., Olaparib). Utilizing patient-derived models of cancer, we are actively investigating DDR-altered, pancreatic tumor cell lines and exploring the relationship between DDR-alterations and HDR-deficiency with three goals: [1] To evaluate the prevalence of HDR-proficiency in BRCA-altered tumors, [2] to understand the extent to which patient-derived models of cancer are concordant and predictive of clinical outcomes, and [3] to identify novel therapeutic strategies for resistant patients. So far, we have observed HDR-proficiency by functional assays (e.g., RAD51 foci formation) in DDR-altered patient-derived cell lines that corresponds with poor response to Olaparib in vitro, and resistance to platinum therapy clinically. Whereas DDR-altered HDR-deficient lines had greater sensitivity to Olaparib and platinum therapy. These early data suggest that measures of HDR by functional assay may be more predictive of clinical therapeutic responses than the use of genetic signatures alone. Citation Format: James R. Carroll, Jason M. Link, Jonathan R. Brody. Characterizing the relationship between genotype and phenotype in DNA damage response-altered pancreatic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3494.
Adeno-Associated Virus Serotype 2–hCHM Subretinal Delivery to the Macula in Choroideremia
Authors: Tomas S. Aleman, Rachel M. Huckfeldt, Leona W. Serrano, Denise J. Pearson, Grace K. Vergilio, Sarah McCague, Kathleen A. Marshall, Manzar Ashtari, Tu M. Doan, Carol A. Weigel-DiFranco, Bethany S. Biron, Xiao-Hong Wen, Daniel C. Chung, Emily Liu, Kevin Ferenchak, Jessica I.W. Morgan, Eric A. Pierce, Dean Eliott, Jean Bennett, Jason Comander, Albert M. Maguire
Journal: Ophthalmology (2022)
Abstract 1127: Effect of the combined therapy of sotorasib and metformin in non-small cell lung cancer cell lines
Authors: Norma Yanet Hernandez-Pedro, Jose Lucio-Lozada, Pedro Barrios-Bernal, Maritza Ramos-Ramírez, Oscar Arrieta
Journal: Cancer Research (2022)

Abstract KRAS is the most frequently mutated oncogene in lung adenocarcinoma, in which is related to poor treatments response and worse survival rates than other driver mutations. KRAS activates MAPK and mTOR pathways, and even after sotorasib treatment, a novel KRAS inhibitor, the duration of responses to this monotherapy are excessively short. In this context, metformin is able to inhibit PI3K and mTOR pathways; therefore, combined use of metformin with sotorasib aids to diminish the activity of both signaling pathways. We performed a dose-effect curve to determine IC50 of sotorasib, and IC10 of metformin to treat lung cancer cell lines harboring different mutational profiles: A549 (KRAS G12S), and H522 (TP53) in order to study the effects of the combination compared to the monotherapy of each drug at MTT assay and western blot analysis. In detail, we evaluated drug-induced cytotoxicity, apoptosis, and activity of MAPK and mTOR pathways. Our results show a synergic effect in cytotoxicity by MTT assay, as well as increased inhibition of MAPK pathway inhibition at combinational treatment, compared to monotherapies in A549 cell lines; conversely, we did not find significant effects on cytotoxicity and signaling inhibition in H522 cell line. In conclusion, the combined treatment of metformin and sotorasib show synergistic effects in drug-induced cytotoxicity and inhibition of MAPK pathways in lung cancer cell lines. Citation Format: Norma Yanet Hernandez-Pedro, Jose Lucio-Lozada, Pedro Barrios-Bernal, Maritza Ramos-Ramírez, Oscar Arrieta. Effect of the combined therapy of sotorasib and metformin in non-small cell lung cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1127.
Abstract 1157: Uncovering transcriptional changes related to cisplatin treatment and mixing of TNBC subclones using single-cell RNA sequencing
Authors: Shadae Nicholas, Patience Mukashyaka, Pooja Kumar, Jeffrey Chuang, Edison Liu
Journal: Cancer Research (2022)

Abstract Triple negative breast cancer (TNBC) has long been characterized by having a high degree of intratumoral heterogeneity. While significant contributions have been made in understanding the components of TNBC tumors, examining the dynamics of interaction between subclones in TNBC is relatively unexplored. By using single-cell RNA sequencing (scRNA-seq) technology, this study aims to focus on understanding changes in gene expression of two TNBC subclones: the cisplatin-resistant subclone (A50) and cisplatin-sensitive subclone (B), when cocultured in 3D organoids in the presence and absence of cisplatin. We hypothesized that there will be significant differentially expressed genes (DEGs) due to various concentrations of cisplatin and mixing effect. We found DEGs (ACTB, FOS, EIF5, BRD2, MAFG, SF3B4, ID1, MGMT, DDIT4 and LPP) due to treatment with cisplatin in both subclones, with the largest clear effect present at a high concentration of cisplatin. Additionally, the network analysis showed that cisplatin was an upstream regulator for 11 DEGs. Even though, gene expression changes due to mixing are much more subtle than effects due to treatment, we saw some DEGs caused by the mixing effect like MT1X which is related to cisplatin resistance. Taken together, the findings of this project will help in future studies when deducing which genes to target in TNBC chemotherapy treatments based on predictive molecular biomarkers. Citation Format: Shadae Nicholas, Patience Mukashyaka, Pooja Kumar, Jeffrey Chuang, Edison Liu. Uncovering transcriptional changes related to cisplatin treatment and mixing of TNBC subclones using single-cell RNA sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1157.
Breakthrough Therapy Designation Criteria Identify Drugs that Improve Clinical Outcomes for Patients: A Case for More Streamlined Coverage of Promising Therapies
Authors: Grace Collins, Mark Stewart, Brittany McKelvey, Hillary Stires, Jeff Allen
Journal: Clinical Cancer Research (2022)

Abstract The breakthrough therapy designation (BTD) process was created to expedite clinical development timelines for drugs intended to treat serious conditions and preliminary clinical evidence indicates the drug may demonstrate substantial improvement over existing therapies. This analysis demonstrates that BTD is a valuable tool for expediting approval of promising therapies in oncology. By comparing drugs indicated to treat non–small cell lung cancer (NSCLC) approved with BTD or without BTD between January 2013 and October 2021, BTD drugs reduced the risk of death by a median of 31% and progression by a median of 48%, while drugs never receiving BTD reduced the risk of death and progression by a median of 15% and 41.9%, respectively. These findings show that BTD criteria accurately identify drugs that improve long-term outcomes for patients with cancer and warrant coordinated efforts to ensure timely coverage decisions and access for patients.
Abstract 1450: Interactions of <i>DNMTs</i> genetic variants associated with breast cancer risk
Authors: Hui-Yi Lin, L. Joseph Su, Lora J. Rogers, Gail A. Runnells, Ping-Ching Hsu, Shelbie D. Stahr, Tung-Chin Chiang
Journal: Cancer Research (2022)

Abstract Background: DNA methyltransferases (DNMTs) control DNA methylation and impact gene expression. Many studies have demonstrated that genetic variants in DNMT genes play a role in cancer development, including breast cancer. However, the impact of SNP-SNP interactions for DNMTs associated with breast cancer risk is unclear. The objective is to evaluate SNP-SNP interactions associated with breast cancer risk. Methods: We selected 14 SNPs in 3 DNMT genes (DNMT1, DNMT3A, and DNMT3B) for the 4,195 women (1:2 match for breast cancer cases and controls), including 1,085 African Americans (AAs) and 3,110 European Americans (EAs) in the Arkansas Rural Community Health (ARCH) cohort. We included different inheritance models (dominant, recessive, and additive) for individual SNP effects, using logistic regressions with breast cancer status (yes/no) as the outcome. Two-way SNP-SNP interactions associated with breast cancer risk were analyzed using the SNP Interaction Pattern Identifier (SIPI) approach developed by our research team. Results: Out of the 14 DNMTs SNPs, we found two SNPs (rs7605753 and rs10196635 in DNMT3A) were individually associated with breast cancer risk (p&amp;lt;0.05) in EAs, however, none was statistically significant in AAs. Interestingly, we applied the SIPI approach, targeting SNP-SNP interactions,19 SNP-SNP interaction pairs for EAs, and 6 pairs for AAs associated with breast cancer risk. These promising SNP interaction pairs had an interaction p-value less than 0.05, far less than the p-values of the 2 constituent SNPs. Also, these promising SNP-SNP interaction pairs are different between races. For example, the EA women with the CC + AT/TT genotype in rs12991495 + rs10196635 (both in DNMT3A) had a higher risk of breast cancer risk than other genotype combinations (Odds ratio [OR]=2.2, p=0.011). On the other hand, the AA women with the TT+AA genotype in the SNP pair of rs2304429 (DNMT3A) + rs2290684 (DNMT1) tend to have a higher breast cancer risk than other genotype combinations in the same pair (OR=4.3, p=0.034). Notably, the individual effects of the two constituent SNPs are not significant (p=0.537 and 0.547). Conclusion: Our findings support that the SNPs in DNMT genes play an essential role in breast cancer risk. SIPI is an excellent tool to evaluate SNP-SNP interactions, which can better predict breast cancer risk. Citation Format: Hui-Yi Lin, L. Joseph Su, Lora J. Rogers, Gail A. Runnells, Ping-Ching Hsu, Shelbie D. Stahr, Tung-Chin Chiang. Interactions of DNMTs genetic variants associated with breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1450.
Assessing acceptability and identifying barriers and facilitators to implementation of the EULAR recommendations for patient education in inflammatory arthritis: a mixed-methods study with rheumatology professionals in 23 European and Asian countries
Authors: Sarah E Bennett, Heidi A Zangi, Ingrid Larsson, Catherine Beauvais, Carina Boström, Andrea Domján, Yvonne van Eijk-Hustings, Kristien Van der Elst, Françoise Fayet, Ricardo J O Ferreira, Mie Fusama, Mariela Geneva-Popova, María del Carmen Herrero Manso, Kirsten Hoeper, Bethan Jones, Marja Leena Kukkurainen, Suet Kei Gladys Kwok, Patricia Minnock, Tiziana Nava, Jette Primdahl, Roopa Rawat, Matylda Sierakowska, Michaela Stoffer-Marx, Astrid van Tubergen, Mwidimi Ndosi
Journal: Annals of the Rheumatic Diseases (2022)

Objectives To disseminate and assess the level of acceptability and applicability of the European Alliance of Associations for Rheumatology (EULAR) recommendations for patient education among professionals in rheumatology across Europe and three Asian countries and identify potential barriers and facilitators to their application. Methods A parallel convergent mixed-methods design with an inductive approach was used. A web-based survey, available in 20 different languages, was distributed to health professionals by non-probability sampling. The level of agreement and applicability of each recommendation was assessed by (0–10) rating scales. Barriers and facilitators to implementation were assessed using free-text responses. Quantitative data were analysed descriptively and qualitative data by content analysis and presented in 16 categories supported by quotes. Results A total of 1159 completed the survey; 852 (73.5%) were women. Most of the professionals were nurses (n=487), rheumatologists (n=320), physiotherapists (n=158). For all recommendations, the level of agreement was high but applicability was lower. The four most common barriers to application were lack of time, lack of training in how to provide patient education, not having enough staff to perform this task and lack of evaluation tools. The most common facilitators were tailoring patient education to individual patients, using group education, linking patient education with diagnosis and treatment and inviting patients to provide feedback on patient education delivery. Conclusions This project has disseminated the EULAR recommendations for patient education to health professionals across 23 countries. Potential barriers to their application were identified and some are amenable to change, namely training patient education providers and developing evaluation tools.
Effect of Care Management or Online Dialectical Behavior Therapy Skills Training vs Usual Care on Self-harm Among Adults With Suicidal Ideation
Authors: M. David Rudd
Journal: JAMA (2022)

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Abstract 3304: Gene expression profiling of full-thickness skin after FLASH proton radiotherapy
Authors: Anastasia Velalopoulou, Ilias V. Karagounis, Giorgos Skoufos, Ioannis I. Verginadis, Michele Kim, Khayrullo Shoniyozov, Artemis G. Hatzigeorgiou, Eric Diffenderfer, Lei Dong, James Metz, Constantinos Koumenis, Keith A. Cengel, Amit Maity, Theresa M. Busch
Journal: Cancer Research (2022)

Abstract Purpose: To investigate the transcriptomic changes induced by FLASH proton radiotherapy (F-PRT) that could be responsible for the protection of normal epithelial tissues by radiation-induced toxicities as have been previously shown by us and others. Methods: C57BL/6J mice received 30 Gy of F-PRT or S-PRT to the hind leg at respective dose rates of 69-124 Gy/sec or 0.39-0.65 Gy/sec. RNA sequencing was performed using full-thickness leg skin at 5 days after radiation revealing major pathways regulated by F-PRT and S-PRT. In an endeavor to identify the full repertoire of cells and gene expression profiles that are involved in the sparing effects of FLASH PRT, we expanded our studies to include single-cell RNA sequencing (sc-RNA seq) and examined additional time points such as Day 2 and Day 10 after radiation. Single-cell transcriptome libraries were generated on a 10X Genomics Chromium system. Datasets were acquired from cell samples derived and sequenced from pooled skin samples of three mice per group. Skin from the sequenced mice was also embedded for spatial analysis of gene expression. Results: RNA sequencing revealed that F-PRT uniquely upregulates almost four times more genes compared to S-PRT (F-PRT-uniquely upregulated 489 genes vs S-PRT-uniquely upregulated 129 genes). Also, F-PRT uniquely downregulated 178 genes, compared to the 125 genes uniquely downregulated by S-PRT. GO analysis demonstrates that the keratinization and apoptosis pathways are uniquely upregulated by S-PRT, whereas F-PRT uniquely upregulates genes involved in vascular development pathway. During submission of the abstract, analysis of sc-RNA seq samples was pending. Conclusion: Our comprehensive studies inform on the transcriptomic profiling of skin cell populations that are affected by F-PRT vs S-PRT; this insight will further spur discoveries on the biology of FLASH radiotherapy effects. Citation Format: Anastasia Velalopoulou, Ilias V. Karagounis, Giorgos Skoufos, Ioannis I. Verginadis, Michele Kim, Khayrullo Shoniyozov, Artemis G. Hatzigeorgiou, Eric Diffenderfer, Lei Dong, James Metz, Constantinos Koumenis, Keith A. Cengel, Amit Maity, Theresa M. Busch. Gene expression profiling of full-thickness skin after FLASH proton radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3304.